Process for preparing polymorph F of sodium neridronate

Abstract

The present invention relates to a novel process for the preparation of a crystalline polymorph of sodium neridronate in hemihydrate form F, comprising the following steps: a) reacting 6-aminocaproic acid with a mixture of phosphorous acid and methanesulfonic acid at a temperature in the range of 60°C to 80°C under stirring until a clear solution is obtained; b) adding phosphorus trichloride to the solution of step (a) at a temperature in the range of 60°C to 80°C under stirring; c) diluting the reaction mixture obtained from the previous step (b) with water and heating the water-diluted mixture at a temperature in the range of 80°C to 120°C; d) cooling the heated mixture obtained in step (c) until room temperature, diluting it with water and then slowly adding aqueous sodium hydroxide solution until a pH in the range from 4.2 to 4.6, to obtain a neutralized solution; e) bringing the neutralized solution of step (d) to a temperature of about 70°C and then subjecting it to a temperature increase in the range from 70°C to 140°C until at least 70% of the initial volume of the neutralized solution of step (d) evaporates, thereby obtaining a suspension that will remain under stirring for at least 1 hour; f) cooling the suspension of step (e) until a temperature in the range from about 5°C to 25°C; and g) recovering crystalline sodium neridronate in hemihydrate form F by filtering the suspension in the previous step (f). The process is particularly simple, scalable and environmentally sustainable.

Description

Field of the Invention

[0001] The present invention relates to a process for preparing crystalline polymorphs of sodium neridronate.

[0002] background

[0003] Neridronic acid sodium is the sodium salt of neridronic acid, and its IUPAC name is 6-amino-1-hydroxy-1,1-hexanediphosphonic acid.

[0004] Neridronate sodium is represented by the following structural formula:

[0005]

[0006] Neridronic acid belongs to the group of bisphosphonates, specifically the aminobisphosphonates.

[0007] Bisphosphonates, in particular aminobisphosphonics, and pharmaceutically acceptable salts thereof, are an important class of drugs useful in the treatment of various pathologies of the musculoskeletal system and calcium metabolism.

[0008] In particular, the therapeutic properties of bisphosphonates depend on their high affinity for hydroxyapatite crystals, the main component of bone, to which the molecules bind, preventing their resorption.

[0009] Therefore, bisphosphonates are widely used in clinical practice to treat diseases such as osteoporosis, hyperparathyroidism, hypercalcemia due to malignancy, osteolytic bone metastases, myositis ossificans progressive, universal calcinosis, arthritis, neuritis, bursitis, tendinitis, Paget's disease, osteogenesis imperfecta, complex regional pain syndrome (CRPS) or algodystrophy, and other inflammatory diseases.

[0010] Neridronate, particularly in injectable form for intramuscular or intravenous administration, has been used successfully for several years to treat osteogenesis imperfecta, Paget's disease of bone, and dystrophy.

[0011] In order to improve compliance with such drugs, and thus facilitate their uptake by patients, it would be desirable to have a solid form for oral administration.

[0012] The possibility of producing solid pharmaceutical forms for oral administration is generally related to the availability of active pharmaceutical ingredients having adequate stability properties in the solid state.

[0013] For this reason, the possibility of producing a pharmaceutical product based on sodium neridronate in solid form for oral administration is closely linked to the availability of the active ingredient sodium neridronate in solid form that is stable over time.

[0014] The hitherto secret European patent application EP18166508.4 filed by the same applicant described for the first time a synthesis and purification process leading to a stable form of sodium neridronate in a polymorph known as Form F, which can be used for the preparation of oral solid forms.

[0015] Said polymorphic form F of the active ingredient sodium neridronate is a hemihydrate crystalline form which has been shown to be surprisingly stable over time relative to any other polymorphic form previously available, thus allowing the preparation of a new oral solid form of the active ingredient which can be used as an alternative to traditional forms of intramuscular or intravenous injection which are less popular with patients in terms of compliance.

[0016] Therefore, the process described in EP18166508.4 makes an incredible contribution to the availability of an industrial process for the preparation of the clinically important polymorphic hemihydrate Form F of neridronate sodium.

[0017] According to the report in EP18166508.4, when starting from the synthesis step of sodium neridronate, the process comprises the following steps:

[0018] a) reacting 6-aminocaproic acid with a mixture of phosphorous acid and methanesulfonic acid and obtaining a mixture;

[0019] b) adding phosphorus trichloride to said mixture according to step (a) under stirring at a temperature in the range of from 60°C to 80°C, keeping the obtained mixture under stirring at a temperature in the range of from 60°C to 70°C for at least 15 hours;

[0020] c) diluting the reaction mixture obtained from the previous step (b) with water and heating the water-diluted mixture at a temperature ranging from 90° C. to 120° C. for at least 13 hours to obtain a heated mixture;

[0021] d) cooling the heated mixture obtained in step (c) to a temperature below 75° C. and slowly adding sodium hydroxide until a pH in the range from 3 to 5, thereby obtaining a suspension;

[0022] e) cooling the suspension obtained in step (d) to a temperature in the range of 10° C. to 30° C. and then slowly adding ethanol to obtain a precipitate of the sodium salt of sodium neridronate in any crystalline form;

[0023] f) recovering the sodium neridronate in any crystalline form formed in the preceding step (e);

[0024] g) dissolving the solid sodium neridronate in any crystalline form of the previous step (f) in water at a temperature ranging from 70° C. to 90° C. to obtain an aqueous solution of sodium neridronate;

[0025] h) adding a solvent selected from the group consisting of ethanol, 1-propanol and 2-propanol to the aqueous solution obtained in step (g) so that the final volume ratio of water:solvent is in the range of from 1:0.5 to 1:1, thereby obtaining a suspension;

[0026] i) mechanically stirring the suspension obtained in step (h) at a temperature in the range of from 60°C to 95°C;

[0027] 1) recovering the crystalline neridronate sodium in hemihydrate Form F formed in the previous step (i).

[0028] Obviously, the industrial process involves many synthesis and purification steps which require large amounts of solvents.

[0029] It is therefore still desirable to define an industrially optimized process which allows reducing the number of steps, which reduces both the industrial production costs of the active ingredient and the environmental costs, both in terms of energy and chemical consumption.

[0030] The object of the present invention was therefore to provide a new industrially scalable and reproducible process which allows obtaining sodium neridronate in the polymorphic hemihydrate Form F with a reduced number of steps and with low environmental impact. SUMMARY OF THE INVENTION

[0032] The inventors of the present patent application have surprisingly identified an optimized process for preparing the crystalline polymorph in the hemihydrate form F of neridronate sodium, the process comprising the following steps:

[0033] a) reacting 6-aminocaproic acid with a mixture of phosphorous acid and methanesulfonic acid at a temperature in the range of from 60° C. to 80° C. under stirring until a clear solution is obtained;

[0034] b) adding phosphorus trichloride to the solution of step (a) at a temperature ranging from 60° C. to 80° C. under stirring;

[0035] c) diluting the reaction mixture obtained from the previous step (b) with water and heating the water-diluted mixture at a temperature ranging from 80° C. to 120° C.;

[0036] d) cooling the heated mixture obtained in step (c) to room temperature, diluting it with water, and then slowly adding an aqueous sodium hydroxide solution until a pH in the range from 4.2 to 4.6 to obtain a neutralized solution;

[0037] e) bringing the neutralized solution of step (d) to a temperature of about 70° C. and then subjecting it to a temperature increase in the range from 70° C. to 140° C. until at least 70% of the initial volume of the neutralized solution of step (d) evaporates, thereby obtaining a suspension that will remain under stirring for at least 1 hour;

[0038] f) cooling the suspension of step (e) until a temperature in the range of from about 5°C to 25°C; and

[0039] g) Recovering crystalline neridronate sodium in hemihydrate Form F by filtering the suspension of the previous step (f). BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 : XRPD of neridronate sodium as crystalline polymorph hemihydrate Form F.

[0042] Figure 2 : Infrared spectrum of neridronate sodium in its crystalline polymorphic hemihydrate Form F. DETAILED DESCRIPTION OF THE INVENTION

[0044] The inventors of the present patent application have identified a new process for preparing a crystalline hemihydrate form of neridronate sodium, referred to as Form F, which allows the preparation of a pharmaceutical composition in a solid oral form with high patient compliance.

[0045] In particular, the hemihydrate crystalline form F of neridronate sodium is a polymorphic form of neridronate sodium, and its powder X-ray diffraction spectrum (XRPD) shows peaks at characteristic values ​​of 2θ angles of 6.51°, 12.02°, 16.51°, 16.66°, 20.80°, 22.21°, 25.30°, 27.65°, 30.05°, 31.87°, as shown in Figure 1 Obviously.

[0046] The crystals of sodium neridronate in the polymorphic hemihydrate crystalline form F are crystallized in a monoclinic system with the following unit cell parameters: α=90°, β=109.339(2)°, γ=90°, With space group P21 / c. Figure 2 Neridronate sodium in the polymorphic hemihydrate crystalline form F shown in FIG. 1 is also characterized by a typical infrared spectrum obtained using a Fourier transform based infrared spectrometer (FT-IR).

[0047] As described in EP18166508.4, the polymorphic hemihydrate crystalline form F of neridronate sodium is the only polymorph known to date that has proven to be sufficiently stable for use in the preparation of oral solid pharmaceutical forms of neridronate sodium.

[0048] Therefore, it is particularly important to develop an industrially simple, efficient and reproducible process for its preparation.

[0049] The inventors of the present invention have surprisingly developed a new process which overcomes the disadvantages of the process described in EP18166508.4 and in particular allows a significant reduction in the number of steps required to obtain sodium neridronate in hemihydrate form F, while greatly reducing the time, energy and chemical products used for its preparation.

[0050] The process comprises the following steps:

[0051] a) reacting 6-aminocaproic acid with a mixture of phosphorous acid and methanesulfonic acid at a temperature in the range of from 60° C. to 80° C. under stirring until a clear solution is obtained;

[0052] b) adding phosphorus trichloride to the solution of step (a) at a temperature ranging from 60° C. to 80° C. under stirring;

[0053] c) diluting the reaction mixture obtained from the previous step (b) with water and heating the water-diluted mixture at a temperature ranging from 80° C. to 120° C.;

[0054] d) cooling the heated mixture obtained in step (c) to room temperature, diluting it with water, and then slowly adding an aqueous sodium hydroxide solution until a pH in the range from 4.2 to 4.6 to obtain a neutralized solution;

[0055] e) bringing the neutralized solution of step (d) to a temperature of about 70° C. and then subjecting it to a temperature increase in the range from 70° C. to 140° C. until at least 70% of the initial volume of the neutralized solution of step (d) evaporates, thereby obtaining a suspension that will remain under stirring for at least 1 hour;

[0056] f) cooling the suspension of step (e) until a temperature in the range of from about 5°C to 25°C; and

[0057] g) Recovering crystalline neridronate sodium in hemihydrate Form F by filtering the suspension of the previous step (f).

[0058] Optionally, after filtering the suspension of step (g), the solid can be washed with a water / ethanol mixture or pure ethanol and subsequently dried, for example under a nitrogen stream and then under vacuum or by other methods known in the art.

[0059] For the purposes of the present invention, room temperature means a temperature in the range from 15°C to 25°C.

[0060] Preferably, step (a) in which 6-aminocaproic acid is reacted with a mixture of phosphorous acid and methanesulfonic acid is carried out using a volume of methanesulfonic acid per gram of 6-aminocaproic acid in the range from 2 mL to 4 mL, preferably 4 mL per gram of 6-aminocaproic acid.

[0061] Preferably, step (b) of adding phosphorus trichloride is carried out using a stoichiometric excess of phosphorus trichloride relative to 6-aminohexanoic acid, preferably equal to or higher than 2 equivalents.

[0062] Preferably, step (c) of diluting is performed by adding a volume of water which is at least 5 to 10 times the volume of methanesulfonic acid used in step (a), preferably 10 to 20 times said volume.

[0063] Preferably, in step (d), after the heated mixture obtained in step (c) has been cooled to room temperature, the mixture is diluted by adding a volume of water such that the final volume of the mixture before neutralization with sodium hydroxide solution is in the range of from 10 ml to 70 ml per gram of 6-aminocaproic acid reacted in step (a), preferably in the range of from 30 ml to 60 ml per gram of 6-aminocaproic acid. Preferably, the dilution water consists of at least 10% of reactor wash water.

[0064] Preferably, in step (e), the following operation is carried out using a low speed, preferably less than 4°C / h, more preferably less than 2°C / h: the temperature is increased in the range of from 70°C to 140°C until at least 70% of the initial volume of the neutralized solution of solution (d) is evaporated.

[0065] Preferably, the evaporation step (e) is carried out under reduced pressure, wherein the pressure value is not less than about 600 mmHg.

[0066] In a preferred embodiment of the invention, the process comprises a further step of adding water at the end of step (d) and before step (e), i.e. the neutralized solution of step (d) is subjected to a dilution step before being subjected to the heating step provided in step (e). Still more preferably, in said dilution step, the volume of water added is such that after said addition, the final volume of the solution is in the range of from 30 ml to 70 ml per gram of 6-aminocaproic acid reacted in step (a), preferably in the range of from 40 ml to 60 ml per gram of 6-aminocaproic acid.

[0067] As is evident, the new process has the following as main advantages compared to the process described, for example, in EP18166508.4: firstly, the steps involving separation and isolation of the intermediate solid sodium neridronate, in any polymorphic form, to be converted into sodium neridronate in Form F are completely eliminated; and secondly, the use of large amounts of antisolvents, which are used to obtain the precipitation of sodium neridronate in Form F, is completely eliminated.

[0068] With the sequence of steps developed by the inventors of the present invention, this can in fact be achieved and neridronate sodium in form F directly obtained by adequately controlling the intermediate evaporation step (e) as explained above.

[0069] Thus, by a very simple process, the sodium neridronate in crystalline form F is obtained in excellent yield and purity, wherein the yield is usually higher than 90%, with reduced environmental impact and easy industrial scale-up.

[0070] The present invention will now be described with reference to the following examples, which are provided for illustrative purposes only and should not be construed as limiting the present invention.

[0071] Example 1. Preparation of Neridronate Sodium in Hemihydrate Crystalline Form F

[0072] 20 ml of methanesulfonic acid, 1 equivalent of phosphorous acid and 1 equivalent of 6-aminocaproic acid (10 g) were loaded into a jacketed 300 mL reactor equipped with an anchored stirring shaft, a steam condenser connected to a NaOH blastchiller, and a dropping funnel. The mixture was heated to 65° C. (T 夹套 =70°C) and stirred (75 rpm-85 rpm) until completely dissolved. Then 2 equivalents of phosphorus trichloride were slowly added from the dropping funnel under stirring, and the reaction mixture was heated to 65°C (T 夹套=70°C) for 18-24 hours. Then 50 ml of water was slowly added to the reaction mixture, after which the resulting solution was heated to 85-90°C (T 夹套 =95°C) for 18-24 hours and finally cooled to 25°C. The reaction mixture then reaches room temperature, is discharged from the reactor, further diluted with 300 mL of water, and a 10% aqueous NaOH solution is added under stirring until a pH value of 4.4 is obtained. The neutralized solution is then transferred to a jacketed reactor heated to 70°C and equipped with a distillation apparatus. The temperature is raised to T 夹套 = 130 ° C. to distill off about 75% of the volume of water under reduced pressure (600 mbar). During the distillation, a suspension is formed, which is stirred at high speed for a few seconds to remove scale and then heated to atmospheric pressure at T 夹套 =125℃(T 内部 =105 ℃ -110 ℃), stirring at a speed of 75rpm-85rpm for about 1 hour. Finally, the suspension is cooled to a temperature of about 15 ℃, and then filtered under vacuum through a paper filter. The solid remaining on the filter is washed with a 1 / 1 mixture of water / ethanol (8 volumes), and then washed with pure ethanol (3 volumes), and finally treated under vacuum for 10 minutes -15 minutes. A small portion of the still moist product is gently ground and analyzed via XRPD to check the shape of the crystal. The wet solid is then dried at 40 ℃ and 30 mbar for at least 18 hours to determine the yield of the process and the crystalline form of the collected product.

[0073] A yield of about 82% was obtained.

[0074] XRPD analysis was performed with an X'pert PRO PANalytical instrument using Cu-Kα1 radiation, equipped with an X-ray tube with line focus (tube voltage and amperage were set to 40 kV and 40 mA, respectively), and equipped with a 1 / 2° anti-scatter slit, a 1 / 2° divergence slit, a 5.00 mm receiving slit, a 0.04 rad Soller slit, and an X'Celerator RTMS detector. Scans were performed between 3°C and 40° with a step length of 0.0167°. The alignment of the instrument was checked periodically with the aid of a silicon standard, and the sample was prepared by loading the powder top onto a glass sample holder.

[0075] exist Figure 1The diffraction pattern of the obtained solid shown in shows characteristic peaks 2θ at 6.51°, 12.02°, 16.51°, 16.66°, 20.80°, 22.21°, 25.30°, 27.65°, 30.05° and 31.87°, which confirms that the process of the invention allows obtaining sodium neridronate in the crystalline hemihydrate form F.

[0076] The evidence is obtained by Figure 2 This was further confirmed by its infrared spectrum shown in , which was obtained using a Nicolet FT-IR 6700 Thermo Fisher model Fourier transform infrared spectrometer (FT-IR).

[0077] Example 2. Preparation of Neridronate Sodium in Hemihydrate Crystalline Form F

[0078] 40 ml of methanesulfonic acid, 1 equivalent of phosphorous acid and 1 equivalent of 6-aminocaproic acid (10 g) were loaded into a jacketed 300 mL reactor equipped with an anchored stirring shaft, a steam condenser connected to a NaOH rapid freezing device, and a dropping funnel. The mixture was heated to 65° C. (T 夹套 =70°C) and stirred (75 rpm-85 rpm) until completely dissolved. Then 2 equivalents of phosphorus trichloride were slowly added from the dropping funnel under stirring, and the reaction mixture was heated to 65°C (T 夹套 =70°C) for 18-24 hours. Then about 100 ml of water was slowly added to the reaction mixture, after which the resulting solution was heated to 85-90°C (T 夹套 =95°C) for 18-24 hours and finally cooled to 25°C. The reaction mixture is then discharged from the reactor, allowed to reach room temperature, diluted with about 100 ml of water from the reactor wash, and a 30% aqueous solution of NaOH is added under stirring until a pH value in the range of from 4.2 to 4.6 is reached. The neutralized solution is diluted with water up to a volume of 600 mL and then transferred to a jacketed reactor heated to 70°C and equipped with a distillation apparatus. The temperature is raised to T 夹套 = 130°C to distill off about 75% of the volume of water. During the distillation a suspension is formed which is stirred at high speed for a few seconds to remove scale and then at T 夹套 =125℃(T 内部=105 ℃ -110 ℃), stirring at a rate of 75rpm-85rpm for about 1 hour. Finally, the suspension is cooled to a temperature of about 25 ℃, and then filtered under vacuum through a paper filter. The solid remaining on the filter is washed with a 1 / 1 mixture of water / ethanol (8 volumes), and then washed with pure ethanol (3 volumes), and finally treated under vacuum for 10 minutes -15 minutes. A small portion of the still moist product is gently ground and analyzed via XRPD to check the shape of the crystal. The wet solid is then dried at 40 ℃ and 30 mbar for at least 18 hours to determine the yield of the process and the crystalline form of the collected product.

[0079] A yield of about 96% was obtained.

[0080] Furthermore, in this case, the acquisition of XRPD and infrared spectra of the crystalline solid obtained confirmed that said solid consisted only of sodium neridronate in crystalline Form F hemihydrate.

[0081] Example 3. Preparation of Neridronate Sodium in Hemihydrate Crystalline Form F

[0082] 40 ml of methanesulfonic acid, 1 equivalent of phosphorous acid and 1 equivalent of 6-aminocaproic acid (10 g) were loaded into a jacketed 300 mL reactor equipped with an anchored stirring shaft, a steam condenser connected to a NaOH rapid freezing device, and a dropping funnel. The mixture was heated to 65° C. (T 夹套 =70°C) and stirred (75 rpm-85 rpm) until completely dissolved. Then 4 equivalents of phosphorus trichloride were slowly added from the dropping funnel under stirring, and the reaction mixture was heated to 65°C (T 夹套 =70°C) for 18-24 hours. Then about 100 ml of water was slowly added to the reaction mixture, after which the resulting solution was heated to 85-90°C (T 夹套 =95°C) for 18-24 hours and finally cooled to 25°C. The reaction mixture is then discharged from the reactor, allowed to reach room temperature, diluted with about 100 ml of water from the reactor wash, and a 30% aqueous solution of NaOH is added under stirring until a pH value in the range of from 4.2 to 4.6 is reached. The neutralized solution is then diluted with water to a volume of 400 mL and transferred to a jacketed reactor heated to 70°C and equipped with a distillation apparatus. The temperature is raised to T 夹套 = 130°C to distill off about 75% of the volume of water. During the distillation a suspension is formed which is stirred at high speed for a few seconds to remove scale and then at T 夹套 =125℃(T 内部=105 ℃ -110 ℃), stirring at a rate of 75rpm-85rpm for about 1 hour. Finally, the suspension is cooled to a temperature of about 25 ℃, and then filtered under vacuum through a paper filter. The solid remaining on the filter is washed with a 1 / 1 mixture of water / ethanol (8 volumes), and then washed with pure ethanol (3 volumes), and finally treated under vacuum for 10 minutes -15 minutes. A small portion of the still moist product is gently ground and analyzed via XRPD to check the shape of the crystal. The wet solid is then dried at 40 ℃ and 30 mbar for at least 18 hours to determine the yield of the process and the crystalline form of the collected product.

[0083] A yield of about 92% was obtained.

[0084] Furthermore, in this case, the acquisition of XRPD and infrared spectra of the crystalline solid obtained confirmed that said solid consisted only of sodium neridronate in crystalline Form F hemihydrate.

[0085] Thus, as is also evident from the results of the experimental tests carried out, the process object of the present invention is a simple, scalable process which allows obtaining sodium neridronate in the hemihydrate polymorphic form F in excellent yields and is therefore suitable for industrial use in the production of said active ingredient.

Claims

1. A process for preparing sodium neridronate in the form of a crystalline hemihydrate Form F, wherein the crystalline hemihydrate Form F of sodium neridronate shows peaks at characteristic values ​​of 2θ angles of 6.51°, 12.02°, 16.51°, 16.66°, 20.80°, 22.21°, 25.30°, 27.65°, 30.05°, 31.87° in a powder X-ray diffraction spectrum (XRPD), the process comprising the following steps: a) reacting 6-aminocaproic acid with a mixture of phosphorous acid and methanesulfonic acid at a temperature in the range of from 60° C. to 80° C. under stirring until a clear solution is obtained; b) adding phosphorus trichloride to the solution of step (a) at a temperature ranging from 60° C. to 80° C. under stirring; c) diluting the reaction mixture obtained from the previous step (b) with water and heating the water-diluted mixture at a temperature ranging from 80° C. to 120° C.; d) cooling the heated mixture obtained in step (c) to room temperature, diluting it with water, and then slowly adding an aqueous sodium hydroxide solution until a pH in the range from 4.2 to 4.6 to obtain a neutralized solution; e) bringing said neutralized solution of step (d) to a temperature of about 70° C. and then subjecting it to a temperature increase in the range from 70° C. to 140° C., until at least 70% of the initial volume of said neutralized solution of step (d) evaporates, thereby obtaining a suspension that will remain under stirring for at least 1 hour; f) cooling the suspension of step (e) until a temperature in the range of from about 5°C to 25°C; and g) recovering crystalline neridronate sodium in hemihydrate Form F by filtering said suspension of the previous step (f).

2. The process according to claim 1, wherein in step (a), 6-aminocaproic acid is reacted with a mixture of phosphorous acid and methanesulfonic acid using a volume of methanesulfonic acid in the range from 2 mL to 4 mL per gram of 6-aminocaproic acid.

3. A process according to claim 2, wherein in step (a), 6-aminocaproic acid is reacted with a mixture of phosphorous acid and methanesulfonic acid using a volume of 4 mL of methanesulfonic acid per gram of 6-aminocaproic acid.

4. The process according to any one of claims 1 to 3, wherein in step (b) of adding phosphorus trichloride, a stoichiometric excess of phosphorus trichloride is used.

5. The process according to claim 4, wherein in step (b) of adding phosphorus trichloride, a stoichiometric excess of phosphorus trichloride equal to or higher than 2 equivalents relative to 6-aminohexanoic acid is used.

6. The process according to claim 1, wherein the diluting step (c) is carried out by adding a volume of water which is at least 5 to 10 times the volume of methanesulfonic acid used in step (a).

7. The process according to claim 6, wherein the diluting step (c) is carried out by adding a volume of water which is from 10 to 20 times the volume of methanesulfonic acid used in step (a).

8. The process according to claim 1, wherein during step (d), the mixture cooled until room temperature is diluted by adding a volume of water such that the final volume of the mixture is in the range of from 10 ml to 70 ml per gram of 6-aminohexanoic acid of step (a).

9. The process according to claim 8, wherein during step (d), the mixture cooled until room temperature is diluted by adding a volume of water such that the final volume of the mixture is in the range from 30 ml to 60 ml per gram of 6-aminohexanoic acid of step (a).

10. A process according to claim 8 or 9, wherein the water used for dilution consists of at least 10% reactor wash water.

11. The process of claim 1 , wherein in step (e), the temperature is increased in the range of from 70° C. to 140° C. at a rate of less than 4° C. / h until at least 70% of the initial volume of the neutralized solution of step (d) is evaporated.

12. A process according to claim 11, wherein in step (e), the following operation is carried out at a rate of less than 2°C / h: the temperature is increased in the range of from 70°C to 140°C until at least 70% of the initial volume of the neutralized solution of step (d) is evaporated.

13. The process of claim 1, wherein the evaporating of step (e) is carried out at a pressure of not less than about 600 mmHg.

14. The process of claim 1, wherein at the end of step (d) and prior to step (e), the neutralized solution of step (d) is subjected to a dilution step before being subjected to the heating step provided in step (e).

15. A process according to claim 14, wherein in the dilution step, the volume of water added is such that after said addition, the final volume of the solution is in the range of from 30 ml to 70 ml per gram of 6-aminohexanoic acid reacted in step (a).

16. A process according to claim 15, wherein in the dilution step, the volume of water added is such that after said addition, the final volume of the solution is in the range of from 40 ml to 60 ml per gram of 6-aminohexanoic acid reacted in step (a).

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